Infections are a leading cause of morbidity and mortality for millions of older Americans. Emerging biologic and epidemiologic data suggest antimicrobial benefits from vitamin D supplements, and possibly marine omega-3 fatty acids (I-3 FA). However, large, long-term prevention trials with adequate dosing in general populations are not available. The IOM recently called for more research on vitamin D. We propose to take advantage of a large NIH-funded study - the VITamin D and OmegA-3 TriaL (VITAL) - to examine the short- and long-term effects of vitamin D and I-3 FA supplements on infection. We also will examine the effect of vitamin D on plasma levels of human cathelicidin antimicrobial peptide (hCAP18), a potential mechanism for the hypothesized antimicrobial benefits of vitamin D. VITAL is a randomized, double-blind, placebo-controlled, 2x2 factorial trial with 20,000 participants (men age e60y;women e65y). Starting in April 2011 and continuing through July 2012, subjects will be enrolled in a 3-month run-in, during which they will receive placebos. At the end of the run-in, those who remain willing and eligible, and who report having taken at least two-thirds of pills, will be randomly assigned to one of four groups for 5 years: vitamin D3 (2000 IU/d) and fish oil (EPA+DHA, 1 g/d);vitamin D3 and fish oil placebo;placebo vitamin D3 and fish oil;and placebo vitamin D3 and placebo fish oil. At 1-year intervals, participants will receive a new supply of pills and a follow-up questionnaire on compliance, possible side effects, and incidence of endpoints. Primary aims of this ancillary study will address upper respiratory infections (URIs) and require the timely creation of a subcohort (10% sample, n=2,000) in early 2012. This URI subcohort will receive special mailings in Feb/Mar 2012 (baseline), Oct/Nov 2012, and Feb/Mar 2013 (same season, 1 year later). The latter mailings will collect details about recent URIs (e.g., severity, duration of illness, treatments). We will collect baseline and 1-year follow-up blood specimens to test for changes in 25(OH)D, I-3, and hCAP18 levels. These data will answer several questions, including whether vitamin D increases hCAP18 levels, and whether this change mediates the hypothesized reduction in URIs. Secondary aims will examine several other types of infections (pneumonia &influenza, urinary tract infections, skin, any antimicrobial-treated infection, infection-related hospitalizations/sepsis), which we will confirm by CMS linkage. In a subset of 250 cases of each outcome, we will further confirm endpoints by supplemental questionnaire. Long-term follow-up will allow us to address the emerging concern that an early beneficial effect could be followed by a weakening or even reversal of benefit with prolonged supplementation. The current study presents a highly efficient and innovative strategy to evaluate vitamin D and I-3 FA supplementation for short- and long-term prevention of infectious diseases, and to test hCAP18 as a potential mechanism. The findings may have direct clinical and public health impact for the prevention of infections in older adults. PUBLIC HEALTH RELEVANCE: The purported health benefits of vitamin D and omega-3 fatty acids are receiving increasing attention in the medical literature and popular press. However, definitive data on the health benefits and risks of these agents are lacking. Findings from this large clinical trial will clarify the role of vitamin D and omega-3 fatty acid supplements in the prevention of respiratory infections and other major infectious diseases in men and women.